PROJECT SUMMARY/ABSTRACT The Role of DOMINO in Regulation of Circadian Rhythms in Drosophila Circadian clocks coordinate daily rhythms in physiology, metabolism, and behavior to enable organism on Earth to anticipate daily environmental changes. Disruptions of circadian clocks have been linked to many diseases, including obesity and diabetes, cardiovascular diseases, neurodegenerative diseases, and even cancers. Studying the mechanisms underlying circadian rhythms has profound significance in basic biology and for human health. Robust cycling in clock controlled gene expression is critical for circadian timekeeping. The long-term goal is to understand how circadian gene expressions are regulated. The core of the circadian pacemaker is highly conserved from Drosophila to human, and these mechanisms were in great part discovered in flies. Previous studies in the lab indicate that domino (dom), which encodes for the SWR1-type nucleosome chromatin remodeling factor, is a novel clock gene in Drosophila. Mutants of dom abolish normal locomotor activity rhythms. DOM protein plays a critical role in transcriptional regulation by replacing the histone H2A with the H2A.V variant. An exchange of the H2A variant with H2A affects nucleosome mobility and positioning, thus regulating transcription. Furthermore, DOM interacts with a critical circadian clock protein- CLOCK (CLK) in Drosophila S2 cells. These findings lead to our hypothesis that DOM acts in the circadian clock through binding to CLK and activating the transcription of clock-controlled genes. This proposal seeks to: 1) define the role of DOM in the control of Drosophila circadian rhythms. 2) elucidate the mechanism of DOM in the control of circadian rhythms. This proposal will combine a set of genetics, epigenetics, molecular biology and genome wide approaches as well as behavior assays to dissect the role of DOM and its function mechanism in flies circadian clock. The mechanisms of circadian timekeeping are highly conserved from fly to human. These studies will hopefully reveal a novel mechanism of the circadian clock by chromatin remodeling and will advance understanding of circadian clocks. These findings will likely have significant implications for understanding human circadian clock, as well as disorders related to defects of chromatin remodeling and disruption of circadian clock.